Transplantation of human or animal pluripotent stem cells (PSCs) or their derivatives to model animals constitutes an important preclinical system to model and investigate cell survival, development and differentiation in vivo, and to assess the safety and efficacy of transplantation-based cell therapies. Immunodeficient mice are dominantly used in biomedical research as hosts for allogeneic and xenogeneic tissue grafts. In this STTR project, we propose to develop a large animal immunodeficient model, i.e. the rabbits. We propose to apply our expertise in CRISPR/Cas9 mediated gene targeting to knockout Foxn1, Rag2, Il2rg and Prkdc in rabbits. We also propose to test the feasibility of developing inducible immunodeficient rabbits. Rabbit is a useful model for regenerative medicine. It has been used to study a number of human diseases that can be treated with regenerative medicine. Immunodeficient rabbits, if successfully developed, can help develop procedures to assess the safety of stem cell therapies over clinically relevant time frames. They can be potentially important research tools to facilitate long-term follow-up studies of immune responses, xenotransplantation, stem cells, and cancer, thus constituting a remarkable preclinical model.